PROJECT SUMMARY Malignant melanoma is one of the most aggressive types of skin cancer, causing a large majority of skin-cancer related deaths worldwide. Recently, there have been staggering breakthroughs with the advent of drugs that act on checkpoint inhibitors. These are paradigm- shifting immunotherapeutic agents not only for melanoma, but for cancers in general, because they harness the body's innate ability to target and destroy malignant cells. The original FDA approval for anti-CTLA-4 and anti-PD-1 therapies for melanoma contributed to better patient outcomes. The recent FDA approval for their combination for metastatic melanoma showed that attacking cancers through dual pathways led to better efficacy than with any single agent alone. Although promising, the incidence of high-grade immune-related adverse events (irAEs) due to the combination therapy is over 50%. Therefore, there is a pressing clinical need to develop therapeutic agents that may enhance the therapeutic effect of anti-PD1 therapy without significantly increasing toxicity in cancer patients. Resiquimod is TLR 7/8 agonist that is chemically related to imiquimod (Aldara). Resiquimod is more potent than imiquimod in inducing cytokine release owing to its ability to target two, not one, TLRs and its increased bioavailability. Our goal is to harness this small molecule to destroy malignant melanocytes, but to keep its effects localized to the site of injection to prevent systemic side effects. In addition, we plan to boost resiquimod with chemical enhancers that will increase the local anti-tumor immune response. Our preliminary data demonstrate that topical resiquimod has surprisingly potent therapeutic efficacy against established melanoma in multiple genetically engineered mouse (GEM) and syngeneic melanoma mouse models. Topical resiquimod treatment not only inhibited melanoma growth, but also suppressed lymph node metastasis while exhibiting the abscopal effect, whereby tumors distant from the site of treatment were also affected. We plan to develop an injectable form of resiquimod, which we believe will be even more effective against melanomas. Our goal is to minimize the dose of resiquimod needed to induce a local anti-melanoma immune response. We will formulate the safest and most effective form of injectable resiquimod first and test our best resulting product with anti-PD1 therapy. We are confident based on our preliminary data that combination injectable resiquimod/anti-PD1 treatment will be groundbreaking for melanoma as well as for many other malignancies such as lung and bladder cancers. We have the scientific and personnel capability to achieve these aims quickly and meticulously. Our innovative product will lay a solid foundation for IND-enabling studies that will ultimately bring a novel and effective therapy to clinicians and patients in their fight against melanoma.